The problem of drug resistance in cancer patients has been well in mind from the beginning of modern medicine and oncology treatments with the so called conventional cytotoxic therapy. With the advent of target therapy against tumor angiogenesis and in particular against the vascular endothelial growth factor (VEGF)/VEGF receptor system, researchers thought that resistance could be no more a problem, since the low pattern of proliferation displayed by endothelial cells. However, beside the efficacy demonstrated by antiangiogenic drugs, resistance during prolonged drug treatments appears as a limiting feature. Nowadays, various mechanisms of resistance to antiangiogenic therapeutics have been discovered, either innate and depending on the host, or acquired by the tumor cells, especially as a consequence of induced hypoxia by antiangiogenic drugs and the redundancy of proangiogenic factors in the tumor microenvironment, and other forms of tumor neovascularization, than sprouting angiogenesis. Here, we have reviewed the preclinical and clinical evidence for mechanisms of resistance to antiangiogenic drugs reported so far. The knowledge of the mechanisms underneath antiangiogenic drug resistance could be of help in the choice of the more appropriate drug, the development of novel therapeutic strategies, the design of proper drug combination protocols or new formulations of antiangiogenic strategies.